2-amino-1,4-dihydropyridine derivatives

ABSTRACT

2-Amino-1,4-dihydropyridines bearing a carbonyl function in the 5-position and being optionally substituted by lower alkyl or phenyl in the 6-position, and the corresponding 2-amino1,4,5,6,7,8-hexahydro-5-oxoquinolines, which derivatives are further substituted by a carbonyl group in the 3-position and optionally substituted in the 4-position by lower alkyl, phenyl, substituted phenyl or a heterocyclic group are antihypertensive agents and coronary vessel dilators. The compounds, of which 2amino-6-methyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5dicarboxylic acid 3,5-diethyl ester is a representative embodiment, are prepared through condensation of an ylideneacetoacetic acid ester and an amidine.

United States Patent [191 Meyer et al.

[451 Dec. 31, 1974 I [22] Filed:

l Z-AMINO- 1 ,4-DIHYDROPYRIDINE DERIVATIVES [75] Inventors: Horst Meyer; Friedrich Bossert,

' both of Wuppertal-Elberfeld; Wulf Vater, Opladen; Kurt Stoepel, Wuppertal-Vohwinkel, all of Germany [73] Assignee: Bayer Aktiengesellschaft,

Leverkusen, Germany Mar. 27, 1974 [21] Appl. No.2 455,304

Related US. Application Data [62] Division of Ser. No. 336,639, Feb. 28, 1973.

[56] References Cited UNITED STATES PATENTS 3,708,489 l/l973 Rucker et al. 260/2955 R 3,773,773 11/1973 Bossert 260/2955 R 3,775,422 1 1/1973 Bossert et al. 260/2949 3,799,936 3/ 1974 Meyer et al 260/2955 R Primary Examiner-Alan L. Rotman [5 7 ABSTRACT 2-Amino-1,4-dihydropyridines bearing a carbonyl function in the 5-position and being optionally substituted by lower alkyl or phenyl in the 6-position, and the corresponding 2-amino-1,4,5,6,7,8-hexahydro-5- oxoquinolines, which derivatives are further substituted by a carbonyl group in the 3-position and optionally substituted in the 4-position by lower alkyl, phenyl, substituted phenyl or a heterocyclic group are antihypertensive agents and coronary vessel dilators. The compounds, of which 2-amino-6-methyl-4-(3- nitrophenyl)-1,4-dihydropyridine-3 ,5 -dicarboxylic acid 3,5-diethyl ester is a representative embodiment, are prepared through condensation of an ylideneacetoacetic acid ester and an amidine.

4 Claims, No Drawings 'AW -DIHYPRQWRID NE 'PEBIYATIYE This is a division of application Ser. No. 336,639 filed Feb. 28, 1973.

DETAILED DESCRIPTION wherein R is hydrogen; lower alkyl; lower alkenyl; lower alkynyl; phenyl; substituted phenyl in which .the substituents are one to three members selected from the group consisting of lower alkyl, lower alkoxy, halogeno, nitro, cyano, trifluoromethyl, azido, carbo(lower alkoxy),.lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, or phenyl; naphthyl; or a heterocyclic ring selected from the groupconsisting of quinolyl, isoquinolyl, py-ridyl, pyrimidyl, themy], furyl and pyrryl, said heterocyclicring being unsubstituted or substitutedby one or two members selected from the group consisting of lower al kyl, lower alkoxy and halogeno;

R, when taken independently, is hydrogen, lower alkyl, phenyl or-pyridyl;

R when takenindependently, is lower alkyl, lower alkoxy lower alkoxy(lower alkoxy), lower alkenyloxy, lower alkynyloxy, amino, lower alkylamino or di(lower alkyl)amino,

R andR when taken togetherare alkylene of 2 to 4 carbon atoms; and

R is lower alkyl,- lower alkoxy, lower alkoxy(lower alkoxy), lower 'alkenyloxy, lower alkynyloxy,

amino, loweralkylamino or di(lower alkyl)amino.

The term lower alkyl denotes a univalent saturated branched or straight hydrocarbon chain containing from 1 to 6 carbon atoms. Representative of such lower alkyl groups are thus methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.butyl, tert.butyl, pentyl, isopentyl, neopentyl, tertpentyl, hexyl, and the like.

The term lower alkenyl denotes a univalent branched or straight hydrocarbon chain containing from two to six carbon atoms and nonterminal ethylenic unsaturation as, for example, vinyl, allyl, isopropenyl, Z-butenyl, 3-methyI-2-butenyl, 2-pentenyl, 3-pentenyl, 2-hexenyl, 4-hexenyl, and the like, preferably having two to four carbon atoms.

The term lower alkynyl denotes a univalent branched or straight hydrocarbon chain containing from two to six carbon atoms and nonterminalacetylenic unsaturation as, for example, ethynyl, 2-propynyl, 4-pentynyl, and the like, preferably having two to four carbon atoms.

The term lower alkoxy denotes a straight or branched hydrocarbon chain bound to the remainder of the molecular through an ethereal oxygen atom as, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy and hexoxy.

The term lower alkylthio denotes a branched or straight hydrocarbon chain bound to the remainder of the molecule through a divalent sulfur as, for example, methylthio, ethylthio, propylthio," isopropylthio, hutylthio, and the like.

The term halogen denotes the substituents fluoro, chloro, bromo and iodo.

As indicated, the present invention also pertains to the physiologically acceptable non-toxic acid addition salts of these basic compounds. Such salts include those derived from organic and inorganic acids such as, without limitation, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulphonic acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic acid, embonic acid, enanthic acid, and the like.

According to the present invention, the foregoing compounds are prepared by reacting a dicarbonyl compound of the formula:

wherein R, R and R are as herein defined, with an amidine of the formula:

in which R is as herein defined. The condensation proceeds smoothly in good yields simply by heating the two components, generally in the presence of an inert organic solvent such as methanol, ethanol, propanol and similar alkanols, ethers such as dioxane and diethyl ether, glacial acetic acid, pyridine, dimethylformamide, dimethylsulfoxide, acetonitrile and the like. The reaction is conducted at temperatures of from 20 to 250C, conveniently at the boiling point of the solvent, and while elevated pressure may be utilized, normal atmospheric pressure is generally satisfactory. The reactants are employed in substantially equimolar amounts. The amidine reactant can be employed as the free base or in the form of a salt such as the hydrohalide salts with the amidine being liberated from the salt through treatment with a basic agent such as an alkali metal alkoxide. The dicarbonyl reagent can be utilized as such or generated in situ by the reaction of an aldehyde of the formula RCHO and a ,B-dicarbonyl compound of the formula RCOCH COR It is rather surprising that the above described condensation produces the desired compounds in such good yields and with such high purity for while it is knownthat a benzylideneacetoacetic acid ester can be condensed with an amino crotonic acid ester to yield a l,4-dihydropyridine (Knoevenagel, Ber. 31, 743, i898), it would be expecte dfrom, for example, Silversmith, J. Org. Chem. 27, 4090 (1952) that the addition of an amidine of an a,B-unsaturated keto compound would yield the dihydropyrimidine derivative rather than the dihydropyridine derivative.

Many of the dicarbonyl compounds utilized as one of the reactants are known to the art and the others can either be generated in situ as herein described or prepared according to methods well known to the art, see for example Org. Reaction XV, 204 et seq. (1967). Typical of this reactant are the following compounds:

benzylideneacetoacetic acid methyl ester,

ethylideneacetoacetic acid methyl ester, isopropylideneacetoacetic acid methyl ester, 2-nitrobenzylideneacetoacetic acid methyl ester, 2-nit'robenzylideneacetylacetone, benzylideneacetylacetone, 3-nitrobenzylideneacetoacetic acid methyl ester, 3-nitrobenzylideneacetoacetic acid propargyl ester, 3-nitrobenzylideneacetoacetic acid allyl ester, 3-nitrobenzylideneacetoacetic acid B-rnethoxyethyl ester,

3-nitrobenzylideneacetoacetic acid B-ethoxyethyl ester,

3-nitrobenzylideneacetoacetic acid isopropyl ester,

3-nitrobenzylideneacetylacetone,

4-nitrobenzylideneacetylacetone,

4-nitrobenzylideneacetoacetic acid B-propoxyethyl ester,

4-nitrobenzylideneacetoacetic acid n-propyl ester,

3-nitro-6-chlorobenzylideneacetoacetic acid methyl ester,

2-cyanobenzylideneacetoacetic acid methyl ester,

2-cyanobenzylideneacetoacetic acid methyl ester,

2-cyanobenzylideneacetoacetic acid ethyl ester, 2-cyanobenzylidenepropionylacetic acid ethyl ester, 3-cyanobenzylideneacetoacetic acid methyl ester, 3-nitro-4-chlo robenzylideneacetylacetone, 3-nitro-4-chlorobenzylideneacetoacetic acid t-butyl ester, 3-nitro-4-chlorobenzylideneacetoacetic acid methyl .ester, 2-nitro-4-methoxybenzylideneacetoacetic methyl ester, 2-cyano-4-methylbenzylideneacetoacetic acid ethyl ester, 2-azidobenzylideneacetoacetic acid ethyl'ester, 3-azidobenzylideneacetylacetone, 2-methylmercaptobenzylideneacetoacetic acid isopropyl ester, 1 2-sulphinylmethylbenzylideneacetoacetic acid ethyl ester,

2-sulphonylbenzylidenemethylacetoacetic acid allyl ester,

4-sulphonylmethylbenzylideneacetoacetic acid ethyl ester,

naphth-l-ylideneacetoacetic acid methyl ester,

naphth-l-ylideneacetoacetic acid ethyl ester,

naphth-2-ylideneacetoacetic acid ethyl ester,

acid

2-ethoxynaphth-l -ylideneacetoacetic acid methyl es ter, 2-methoxynaphth-l-ylideneacetoacetic acid ethyl ester,

5-bromonaphth-l-ylideneacetoacetic acid methyl es ter, quinol-2-ylmethylideneacetoacetic acid methyl ester, quinol-3-ylmethylideneacetoacetic acid methyl-ester, quinol-4-ylmethylideneacetoacetic acid ethyl ester, quinol-8-ylmethylideneacetoacetic acid ethyl ester,

isoquinol-L-ylmethylideneacetoacetic acid ester,

isoquinol-3-ylmethylideneacetoacetic acid methyl ester,

a-pyridylmethylideneacetoacetic acid methyl ester,

wpyridylmethylideneacetoacetic acid ethyl ester,

a-pyridylmethylideneacetoacetic acid allyl ester,

a-pyridylmethylideneacetoacetic acid cyclohexyl ester,

B-pyridylmethylideneacetoacetic acid' B-methoxyethyl ester,

'y-pyridylmethylideneacetoacetic acid methyl ester,

o-methyl-a-pyridylmethylideneacetoacetic acid ethyl ester,

4,6-dimethoxypyrimid-5-ylmethylideneacetoacetic acid ethyl ester,

then-2-ylmethylideneacetoacetic acid ethyl ester,

fur-2-ylmethylideneacetoacetic acid allyl ester,

pyrr-2-ylthylideneacetoacetic acid methyl ester,

nitrobenzylidenepropionylacetic acid ethyl ester,

a-pyridylmethylidenepropionylacetic acid ethyl ester,

a-pyridylmethylidenepropionylacetic acid methyl ester,

a-pyridylmethylideneacetylacetone,

2-, 3- or 4-methoxybenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4methoxybenzylideneacetylacetone,

2-methoxybenzylideneacetoacetic acid allyl ester,

Z-methoxybenzylideneacetoacetic acid allyl ester,

2-meth0xybenzylideneacetoacetic acid propargyl ester,

2-methoxybenzylideneacetoacetic acid fi-methoxyethyl ester,

2-isopropoxybenzylideneacetoacetic acid ethyl ester,

3-butoxybenzylideneacetoacetic acid methyl ester,

3,4,5-trimethoxybenzylideneacetoacetic acid allyl ester,

2-methylbenzylidenepropionylacetic acid methyl ester,

2, 3- or 4-methylbenzylideneacetoacetic acid ethyl ester,

Z-methylbenzylideneacetoacetic methoxyethyl ester,

2-methylbenzylideneacetoacetic acid B-propoxyethyl ester,

2-methylbenzylideneacetylacetone,

3,4-dimethoxy-5-bromobenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-chlorobenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-bromobenzylideneacetoacetic acid ethyl ester,

2-, 3- or 4-fluorobenzylideneacetoacetic acid ethyl ester,

Z-fluorobenzylideneacetoacetic acid methyl ester,

3-chl0robenzylideneacetylacetone,

3-chlorobenzylidenepropionylacetic acid ethyl ester,

3-chlorobenzylideneacetoacetic acid ethyl ester,

methyl acid 62- 2-chlorobenzylideneacetoacetic acid allyl ester,

2-, 3- or 4-trifluoromethylbenzylideneacetoacetic acid isopropyl ester,

3-trifluoromethylbenzylideneacetoacetic acid methyl ester,

2-carbethoxybenzylideneacetoacetic acid ethyl ester,

3-carbomethoxybenzylideneacetoacetic acid methyl ester,

4-carboisopropoxybenzylideneacetoacetic acid isopropyl ester, 4-carbomethoxybenzylideneacetoacetic acid allyl ester,

3-nitrobenzylidenecyclohexane-l ,3-dione, and

3-nitrobenzylidenecycloheptane-l ,3-dione.

The amidine reactantsare simlarly known or can be readily produced according to known methods, see for example McElvain et al., J.A.C.S., 73, 2760 1951). Typical of these reactants are the following:

amidinoacetic acid methyl ester,

amidinoacetic acid ethylest'er,

amidinoacetic acid n-propyl ester,

amidinoacetic-acid isopropyl ester,

amidoacetic acid cyclohexyl ester,

amidinoacetic acidB-methoxyethyl ester,

amidinoacetic acid a-ethoxyethyl ester,

amidinoacetic acidB-ethoxyethyl ester, amidinoacetic acid propargyl ester, and amidinoacetamide.

As noted above, the compounds of thepresent invention demonstrate the ability to reduce blood pressure and to effect a dilation of the coronary vessels. They can accordingly be used where either orboth ofthese effects are desired. Thus uponparenteraLoral or sublingual administration, the compoundsproducea distinct and long'lasting dilation of the coronary vessels which is intensified-by a simultaneous nitritelike effect of reducing the load on the heart. The effect on heart metabolism is thus one of energy saving. In addition, the compounds lower the blood pressure of normotonic and hypertonic animals and can thus be used as antihypertensive agents. These properties can be conveniently observed in well known laboratory models. Thus for example the coronary vessel dilation effect can be observed by measuring the increase in oxygen saturation in the coronary sinus in thenarcotized, heart catheterized dog, as shown in the following table:

4-( 3-nitrophenylll.4-dihydropyridine-3,5-dicarboxylic acid diethyl ester The hypotensive activity of the present compounds can be observed by measuring the blood pressure of hypertensive rats following administration of the compounds. The following table demonstrates the dose which results in at least a mm Hg reduction in blood pressure of such animals:

The toxicity of the compounds is remarkably low. Thus for example the toxic dose of 2-amino-6-methyl- 4-(2rtrifluoromethylphenyl )-l ,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester in mice upon oral administration is greater than l000 mg/kg.

In addition to the effect on blood pressure and coronary vessels, the compounds also lower the excitability of the stimulus formation and excitation conduction system within the heart so that an antifibrillation action is observed at therapeutic doses. The tone of the smooth muscle of the vessels is also greatly reduced. This vascular-spasmolytic action can be observed in the entire vascular system as well as in more or less isolated and circumscribed vascular regions such as the central nervous system. In addition, a strong muscularspasmolytic action is manifested in the smooth muscle of the stomach, the intestinal tract,'the urogenital tract and the respiratory system. Finally, there is some evidence that the compounds influence the cholesterol level and lipid level ofthe blood. These effects complement one another and the compounds are thus highly desirable as pharmaceutical agents to be used in the treatment of hypertension and conditions characterized by a constriction of the coronary blood vessels.

Pharmaceutical compositions for effecting such treatment will contain a major or minor amount, e.g. from to 0.5%, of at least one 2-amino-l,4- dihydropyridine as herein defined in combination with a pharmaceutical carrier, the carrier comprising one or more solid, semi-solid or liquid diluent, filler and formulation adjuvant which is nontoxic, inert and pharmaceutically acceptable. Such pharmaceutical compositions are preferably in dosage unit form; i.e. physically discrete units containing a predetermined amount of the drug corresponding to a fraction or multiple of the dose which is calculated toproduce the desired therapeutic response. The dosage units can contain one, two, three four or more single doses or, alternatively, one-half, third or fourth of a single dose. A single dose preferably contains an amount sufficient to produce the desired therapeutic effect upon administration at one application of one or more dosage units according to a predetermined dosage regimen, usually a whole, half, third or quarter of the daily dosage administered once, twice, three of four times a day. Other therapeutic agents can also be present.

Although the dosage and dosage regimen must in each case be carefully adjusted, utilizing sound-professional judgment and considering the age, weight and condition of the recipient, the route of administration and the nature and gravity of the illness, generally the daily dose will be from about 0.001 to about 2 mg/kg, preferably 0.005 to 1.0 mg/kg, when administered parenterally and from about 0.1 to about 20 mg/kg, preferably ).5 to 10 mg/kg, when admnistered orally. In some instances a sufficient therapeutic effect can be obtained at lower doses while in others, larger doses will be required.

Oral administration can be effected utilizing solid and liquid dosage unit forms such as powders, tablets, dragees, capsules, granulates, suspensions, solutions and the like.

Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate as for example starch, lactose, sucrose, glucose or mannitol. Sweetening, flavoring, preservative, dispersing and coloring agents can also be present.

Capsules are made by preparing a powder mixture as described above and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Tablets are formulated for example by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally with a binder such as carboxymethyl cellulose, an alginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the resulting imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The midicaments can also be combined with free flowing inert carriers and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to thse coatings to distinguish different unit dosages.

Oral fluids such as solutions, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous sucrose solution while elixirs are prepared through the use ofa nontoxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a nontoxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxyethylene sorbitol esters, preservatives, flavor additives such as peppermint oil or saccharin, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulatctl. The forum lation can also be prepared to prolong or sustain the rclease as for example by coating or embedding particulate material in polymers, wax. or the like.

Parenteral administration can be effected utilizing liquid dosage unit forms such as sterile solutions and suspensions intended for subcutaneous, intramuscular or intravenous injection. These are prepared by suspending or dissolving a measured amount of the compound in a nontoxic liquid vehicle suitable for injection such as an aqueous or oleaginous medium and sterilizing the suspension or solution. Alternatively a measured amount of the compound is placed in a vial and the vial and its contents are sterilized and sealed. An accompanying vial'or vehicle can be provided for mixing prior to administration. Nontoxic salts and salt solutions can be added to render the injection isotonic. Stabilizers, preservatives and emulsifiers can also be added.

The following examples will serve to further typify the nature of the present invention through the presentation of specific embodiments. These examples should not be construed as a limitation on the scope of Applicants invention since the subject matter regarded as the invention is set forth in the appended claims.

EXAMPLE 1 Upon boiling a solution of 21.8 g of benzylideneacetoacetic acid ethyl ester and 13.0 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours, 2-amino-6-methyl-4-pheny1-l,4- dihydropyridine-3,S-dicarboxylic acid diethyl ester of melting point 164C (alcohol) is obtained.

Yield: 67% of theory.

EXAMPLE 2 Upon boiling a solution of 24.9 g of 2- nitrobenzylideneacetic acid methyl ester and 13.0 g of amidinoacetic acid ethyl ester in ml of ethanol for 1 hour, 2-amino-6-methyl-4-(2-nitrophenyl)-1,4- dihydropyridine-3,S-dicarboxylic acid 3-ethyl ester 5- methyl ester of melting point 168C (alcohol) is obtained.

Yield: 59% of theory.

EXAMPLE 3 Upon boiling a solution of 24.8 g of 2-methoxybenzylideneacetoacetic acid ethyl ester and 13.0 g of amidinoacetic acid ethyl ester in ml of ethanol for 1 hour, 2-amino-6-methyl-4-(2-methoxyphenyl)l,4- dihydropyridine-3,S-dicarboxylic acid diethyl ester of melting point 170C (ethanol) is obtained.

Yield: 65% of theory.

EXAMPLE 4 Upon boiling a solution of 23.2 g of 2-methylbenzylideneacetoacetic acid ethyl ester and 13.0 g of amidinoacetic acid ethyl ester in 150ml of ethanol for 2 hours, 2-amino-6-methyl-4-(2-methylphenyl)-l,4- dihydropyridine-3,S-dicarboxylic acid diethyl ester of melting point 130C (ethanol) is obtained.

Yield: 71% of theory.

EXAMPLE 5 Upon boiling .a solution of 24.3 g of 2- cyanobenzylideneacetoacetic acid ethyl ester and 13.0 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours, 2-amino-6-methyl-4-(2-cyanophenyl)-1,4- dihydropyridine-3,S-dicarboxylic acid diethyl ester of melting point 208C (ethanol) is obtained.

Yield: 54% of theory.

EXAMPLE 6 Upon boiling a solution of 14.2 g of 2- trifluoromethylbenzylideneacetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 1 hour, 2-amino-6-methyl-4-(2- trifluoromethylphenyl)-l ,4-dihydropyridine-3.5- dicarboxylic acid diethyl ester of melting point 156 (ethanol) is obtained.

Yield: 76% of theory.

' EXAMPLE 7 Upon boiling a solution 12.6 g of 3- chlorobenzylideneacetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours, 2-amino-6-methyl-4-(3-chlorophenyl)-l ,4-

dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 157159C (ethanol) is obtained. Yield: 62% of theory.

EXAMPLE 8 Upon boiling a solution of 13.2 g of 4-methylmercaptobenzylideneacetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 1 hour, 2-amino-6-methyl-4-(4- meth'ylmercaptophenyU-l ,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester of melting point 165C (ethyl acetate/petroleum ether) is obtained.

Yield: 49% of theory.

EXAMPLE 9.

Upon boiling a nitrobenzylideneacetoacetic acid methyl ester and 13.0

g of amidinoacetic acid ethyl ester in 180 ml of ethanol 5 for 1 hour, 2-aminio-6-methyl-4-(3-nitrophenyl)-l,4- dihydropyridine-3,S-dicarboxylic acid 3-ethyl ester 5- methyl ester of melting point 124C is obtained. Yield: 59% of theory.

EXAMPLE 11 Upon heating a solution of 13.8 g of 3- nitrobenzylideneacetoacetic acid isopropyl ester and 6.5 of amidinoacetic acid ethyl ester in' 150 ml of eth- 10 anol for 2 hours, 2-amino-6-methyl-4-(3-nitrophenyl)- 1,4-dihydropyridine-3,S-dicarhoxylic acid 3-ethyl ,5- isopropyl ester of melting point 206207C (alcohol) is obtained. Yield: 62% of theory.

EXAMPLE l2 Boiling a solution of 10.9 g of 3- nitrobenzylideneacetoacetic acid propargyl ester and 5.2 g of amidinoacetic acid ethyl ester in ml ofethanol for 1 hour yields 2-amino-6-methyl-4 (3- nitrophenyl )-l ,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester 5-propargyl ester of melting point 181C (ethanol).

Yield: 59% of theory.

EXAMPLE13 Heating 21 solution of 14.6 g of 3- nitroberizylideneacetoacetic acid B'methoxyethyl ester and 6.5 g of amidinoacetic acid ethyl ester in ml of ethanol for 1 hour yields 2-amino-6-methyl-4-(3- nitrophenyl )-l ,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester S-B-methoxyethyl ester of melting point 179C (ethyl acetate/petroleum ether).

Yield: 58% of theory.

EXAMPLE14.

Upon boiling a solution of 7.6 g of 3- nitrobenzaldehyde, 5.0 g of acetylacetone and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours, 2-amino-5-acetyl-6-methyl-4-(3-nitrophenyl)- 1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 217C (ethanol) is obtained.

Yield: 48% of theory.

iEXAMPLe 15 Upon boiling a solution of 14.2 g of 3-nitro-6- chlorobenzylideneacetoacetic acid methyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 1 hour, 2-amino-6-methyl-4-(3-nitro-6- chlorophenyl )-1 ,4-dihydropyridine-3,5-dicarboxylic acid 3-ethyl ester S-methylester of melting point 124C (ethanol) is obtained.

Yield: 73% of theory.

EXAMPLE 16 Upon boiling a solution of 10.4 g of 2- furfurylideneacetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours. 2-amino-6-methyl-4-(fur-Z-yl)-1,4- dihydropyridine-3,S-dicarboxylic acid diethyl ester of melting point 183C (isopropanol) is obtained.

Yield: 78% of theory.

EXAMPLE 17 Upon boiling a solution of 14.0 g of benzylidenebenzoylacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours, 2- amino-4,6-diphenyl-1,4-dihydropyridine-3,5- dicarboxylic acid ethyl ester of melting point 183C (ethanol) is obtained.

Yield: 48% of theory.

EXAMPLE 18 Upon heating a solution of 15.6 g of ethylideneacetoacetic acid ethyl ester and 13.0 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for Yield: 61% of theory.

2 hours. 2-amino-4,6-dimethyl-1,4-dihydropyridine- 3,5-dicarboxylic acid diethyl ester of melting point 140C (isopropanol) is obtained. Yield: 59% of theory.

EXAMPLE 19 Upon boiling a solution of 2.8 g of acetaldehyde, 5.6 g of cyclohexane-l ,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours, 2- amino-4-methyl-l,4,5,6,7,8-hexahydro-5- oxoquinoline-3-carboxylic acid ethyl ester of melting point 236C (ethanol) is obtained. Yield: 53% of theory.

EXAMPLE 20 Upon boiling a solution of 7.6 g of 3- nitrobenzaldehyde, 5.6 g of cyclohexane-l ,3-dione and 6.5 g of amidinoaceticacid ethyl ester for 1 hour, 2- amino-4-(3-nitrophenyl)-1,4,5,6,7,8-hexahydro-5- oxoquinoline-3-carboxylic acid ethyl ester of melting point 260C is obtained (alcohol/DMF).

EXAMPLE 21 Upon boiling a solution of 7.1 g of 3- chlorobenzaldehyde, 5.6 g of cyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours, 2-amino-4-(3-chlorophenyl)- 1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 266C (ethanol/DMF) is obtained. Yield: 66% of theory.

EXAMPLE 22 Upon boiling a solution of 5.3 g of pyridin-2- aldehyde, 5.6 g of cyclohexane-l,3-dine and 6.5 g of amidinoacetic acid ethyl ester in 150 ml of alcohol for 3 hours, 2-amino-4-(a-pyridyl)-1,4,5,6,7,8-hexahydro- -oxoquinoline-3-carboxylic acid ethyl ester of melting point 260C is obtained (alcohol).

Yield: 46% of theory.

EXAMPLE 23 Upon heating a solution of 7.6 g of 2- nitrobenzaldehyde, 5.6 g of cyclohexane-l ,3-dioneand 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours, 2-amino-4-(2-nitropheny1)- 1,4,5 ,6,7,8-hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester of melting point 212C (alcohol) is obtained.

Yield: 69% of theory.

EXAMPLE 24 Upon heating a solution of 7.9 of quinolin-4- aldehyde, 5.6 g of cyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 3 hours, 2-amino-4-(quinol-4-yl)-1,4,5,6,7,8- hexahydro-S-oxoquinolinecarboxylic acid 3-ethyl ester of melting point 260C (ethanol/DMF) is obtained. Yield: 81% of theory.

EXAMPLE 25 Upon boiling a solution of 5.7 g of 4,6- dimethoxypyrimidin-S-a1dehyde, 3.8 g of cyclohexane- 1,3-dione and 4.4 g of amidinoacetic acid ethyl ester in 80 ml of ethanol for 8 hours, 2-amino-4-(4.6- dimethoxypyrimid-5-yl)-1,4,5,6,7,8-hexahydro-5- oxoquinoline-3-carboxylic acid ethyl ester of melting point 273C (alcohol) is obtained. Yield: of theory.

EXAMPLE 26 Upon boiling a solution of 6.3 g of l-naphthaldehyde, 4.5 g of cyclohexane-1,3-dione and 5.2 g of amidinoacetic acid ethyl ester in 150 ml of ethanol for 2 hours. 2-amino-4-(naphth- 1 -yl)-l ,4,5 .6,7,8-hexahydro-5- oxoquinoline-3-carboxylic acid ethyl ester of melting point 279C (ethanol/DMF) is obtained.

Yield: 64% of theory.

EXAMPLE 27 Upon heating a solution of 6.3 g of isoquinolin-laldehyde, 4.5 g of cyclohexane-l,3-dione and 5.2 g of amidinoacetic acid ethyl ester in ml of ethanol for 2 hours, 2-amino-4-(isoquinol-l-y1)-1,4,5.6,7,8- hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester of melting point 272C (ethanol) is obtained.

EXAMPLE 28 Upon heating a solution of 4.8 g of 6-methylpyridin- 2-aldehyde, 4.5 g of cyclohexane, 1,3-dione and 5.2 g of amidinoacetic acid ethyl ester in ml of ethanol for 8 hours, 2-amino-4-(6-methylpyrid-2-yl)- l,4,5,6,7,S-hexahydro-S-oxoquin0line-3-carboxylic acid ethyl ester of melting point 260C (ethanol/DMF) is obtained. Yield: 46% of theory.

EXAMPLE 29 Upon boiling a solution of 13.3 g of 3- nitrobenzylideneacetoacetic acid ethyl ester and 5.1 g of amidinoacetamide in ml of ethanol for 2 hours, 2-amino-6-methyl-5-carbethoxy-4-(3-nitrophenyl)- 1,4-dihydropyridine-3-carboxylic acid amide of melting point 260C (alcohol) is obtained.

Yield: 52% of theory.

EXAMPLE 3O EXAMPLE 31 Upon heating a solution of 26.3 g of 3- nitrobenzylideneacetoacetic acid ethyl ester and 14.4 g of amidinoacetic acid isopropyl ester in 250 ml ofethanol for 2 hours, 2-amino-6-methyl-4-(3-nitrophenyl)- 1,4-dihydropyridine-3,5-dicarboxylic acid 3-isopropyl ester S-ethyl ester of melting point -6C (ethanol) is obtained. Yield: 77% of theory.

EXAMPLE 32 Heating a solution of 14.3 g of 2-trit'luoromethylben zylideneacetoacetic acid ethyl ester and 7.2 g of amidinoacetic acid isopropyl ester in 150 ml of ethanol for 1 hour yields 2-amino-6-methyl-4-(2- trifluoromethylphenyl)-1,4-dihydropyridine-3.5-

dicarboxylic acid 3-isopropyl ester S-ethyl ester of melting point 106C. Yield: 49% of theory.

EXAMPLE 33 Upon heating a solution of 13.9 g of 3- nitrobenzylideneacetoacetic acid isopropyl ester and 7.2 g of amidinoacetic acid isopropyl ester in 180 ml of ethanol for 1 hour, 2-amino-6-methyl-4-(3- nitrophenyl)-1,4-dihydropyridine-3,S-dicarboxylic acid diisopropyl ester of melting point 122C (ether) is obtained.

Yield: 62% of theory.

EXAMPLE 34 EXAMPLE 35 Upon heating a solution of 12.5 g of 3- nitrobenzylideneacetoacetic acid methyl ester and 7.2 g of amidinoacetic acid isopropyl ester in 150 ml of ethanol for'2 hours, 2-amino-6-methyl-4-(-3-nitrophenyl)- 1,4-dihydropyridine-3,5:dicarboxylic acid 3-isopropyl ester S-methyl ester of melting point 167C (ethanol) is obtained. Yield 82% of theory.

EXAMPLE 36 Upon heating a solution of 11.0 of 2-trifluoromethyl- 4-nitrobenzaldehyde, 5.6 g of cycloheitane-l ,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 250 ml of ethanol of 2 hours, 2-amino-4-(2-trifluoromethyl-4 nitrophenyl )-l .4.5,6,7,8-hexahydro-5-oxoquinoline-3- carboxylic acid ethyl ester of melting point 264C (ethanol) is obtained.

Yield: 62% of theory.

EXAMPLE -37 Heating a solution of 13.2 g of 3- nitrobenzylideneacetoacetic acid ethyl ester and 7.2 g

of amidinoacetic acid n-propyl ester in 200 ml of ethanol for 2 hours yields 2-amino-6-methyl-4-(3- nitrophenyl)-l ,4-dihydropyridine-3,5-dicarboxylic acid 3-n-propyl ester 5-ethyl ester of melting point 168C (ethanol).

Yield: 79% of theory.

EXAMPLE 38 Boiling a solution of 8.5 g of 6-nitroveratraldehyde, 4.0 g of cyclohexane-1,3-dione and 5.2 g of amidinoacetic acid ethyl ester-in 150 ml of ethanol for 1 hour yields '2-amino-4-(2-nitro-4,5-dimethoxyphenyl)- l.4.5,6.7.8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 261C (ethanol). Yield: 52% of theory.

EXAMPLE 39 Boiling a solution of 13.2 g of 3- nitrobenzylideneacetoacetic acid ethyl ester and 8.0 g

of amidinoacetic acid B-methoxyethyl ester in 200 ml of ethanol for 2 hours yields Z-amino-6-methyl-4-(3- nitrophenyl)-l.4-dihydropyridine-3.S-dicarboxylic acid 3-(B-methoxyethyl) ester S-ethyl ester of melting point 174C.

Yield: 59% of theory.

EXAMPLE 40 Upon heating a solution of 6.1 g of biphenyl-2- aldehyde, 3.8 g of cyclohexane-l.3-dione and 5.1 g of amidinoacetic acid ethyl ester in ml of ethanol for 1 hour, 2-amino-4-(biphenyl-2-yl)-145.6.7.8- hexahydro-S-oxoquinoline-3-carboxylic acid ethyl ester of melting point 248C (ethanol) is obtained. Yield: 45%of theory.

EXAMPLE 41 Boiling a solution of 13.4 g of (l-naphthylidene)- acetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 8 hours yields 2-amino-6-methyl-4-( l-naphthyl)-1,4- dihydropyridine-3,5-dicarboxylic acid diethyl ester of melting point 174C (ethanol).

Yield: 62% of theory.

EXAMPLE 42 Upon heating a solution of 11.5 g of 2- cyanobenzylideneacetoacetic acid methyl ester and 7.2 g of amidinoacetic acid isopropyl ester in 100 ml ofethanol for 6 hours. 2-amino-6-methyl-4-(2- cyanophenyl)-1,4-dihydropyridine-3,S-dicarboxylic acid 3-isopropyl ester S-methyl ester of melting point 211C (ethanol) is obtained.

Yield: 72% of theory.

EXAMPLE 43 Upon boiling a solution of 11.5 g of 2- cyanobenzylideneacetoacetic acid methyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 8 hours, 2-amino-6-methyl-4-(2-cyanophenyl)-1.4- dihydropyridine-3,S-dicarboxylic acid 3-ethyl ester 5- methyl ester of melting point 224C (ethanol) is obtained.

Yield: 66% of theory.

EXAMPLE 44 Upon boiling a solution of 14.8 g of 2-phenylbenzylideneacetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 8 hours, 2-amino-6-methyl-4-(biphenyl-2-yl)-l.4- dihydropyridine-3,S-dicarboxylic acid ethyl ester of melting point 182C (ethanol) is obtained.

Yield: 41% of theory.

EXAMPLE 45 Upon heating a solution of 12.5 g of 3 nitrobenzylideneacetoacetic acid methyl ester and 7.2 g of amidinoacetic acid n-propyl ester in 100 ml of ethanol for 6 hours, 2-amino-6-methyl-4-(3-nitrophenyl)- l,4-dihydropyridine-3.S-dicarboxylic acid 3-n-propyl ester 5-methyl ester of melting point C (ethanol) is obtained.

Yield: 69% of theory.

EXAMPLE 46 Upon heating a solution of 12.2 g of (2-thenylidene)- ace'toacetic'acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 4 hours. 2-

amino-6-methyl-4-(2-thenyl)-1,4-dihydropyridine-3,5- dicarboxylic acid diethyl ester of melting point 170C (ethanol) is obtained.

Yield: 73% of theory.

EXAMPLE 47 Upon heating a solution of 10.9 g of benzylideneacetoacetic acid dimethylamide and 5.0 g of amidinoacetamide in 100 ml of ethanol for 8 hours, 2- amino-6-methyl-4-phenyl-5(N,N- dimethylaminocarbonyl)-l ,4-dihydropyridine-3- carboxylic acid amide of melting point 236C (ethanol) is obtained.

Yield: 50% of theory.

EXAMPLE 48 Heating a soution of 10.9 g of benzylideneacetoacetic acid dimethylamide and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of methanol for 6 hours yields 2-amino-6-methyl-4-phenyll ,4-dihydropyridine-3,5- dicarboxylic acid 3-ethyl ester 5-(N,N-dimethylamide) of melting point 230C (alcohol).

Yield: 61% of theory.

EXAMPLE 49 Boiling a solution of 13.2 g of 2- nitrobenzylideneacetoacetic acid ethyl ester and 7.2 g of amidinoacetic acid isopropyl ester in 100 ml of ethanol for 6 hours yields 2-amino-6-methyl-4-(2- nitrophenyl)-l,4-dihydropyridine-3,S-dicarboxylic acid 3-isopropyl ester S-ethyl ester of melting pont 139C (isopropanol).

Yield: 39% of theory.

EXAMPLE 5O Boiling a solution of 13.2 g of 2- nitrobenzylideneacetoacetic acid ethyl ester and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 6 hours yields 2-amino-6-methyl-4-(2-nitrophenyl)- 1,4-dihydropyridine-3,S-dicarboxylic acid diethyl ester of melting point 159C (ethanol).

Yield: 52% of theory.

EXAMPLE 51 Upon heating a solution of 12.5 g of 2- nitrobenzylideneacetoacetic acid methyl ester and 7.2 g of amidinoacetic acid isopropyl ester in 100 ml of ethanol for 8 hours, 2-amine-6-methyl-4-(2-nitrophenyl)- 1,4-dihydropyridine-3,S-dicarboxylic acid 3-isopropyl ester 5-methyl ester of melting point 203C (isopropanol) is obtained.

Yield: 50% of theory.

EXAMPLE 52 Upon heating a' solution of 12.2 g of 2- cyanobenzylideneacetoacetic acid ethyl ester and 7.2 g of amidinoacetic acid n-propyl ester in 100 m1 of ethanol for 8 hours, 2-amino-6-methyl-4-(2-cyanophenyl)- 1,4-dihydropyridine-3,S-dicarboxylic acid 3-n-propyl ester 5-ethyl ester of melting point 182C (ethanol) is obtained.

Yield: 62% of theory.

EXAMPLE 53 Upon heating a solution of 13.9 g of 3- nitrobenzylideneacetoacetic acid isopropyl ester and 7.2 g of amidinoacetic acid n-propyl ester in 100 ml of ethanol for 6 hours, 2-amino-6-methyl-4-(3- nitrophenyl)-1,4-dihydropyridine-3,S-dicarboxylic acid 3-n-propyl ester 5-isopropyl ester of melting point 199C (isopropanol) is obtained.

Yield: of theory.

EXAMPLE54 Heating a solution of 6.5 g of 3-cyanobenzaldehytlc. 5.6 g of cyclohexane-l ,3-dione and 6.5 g of amidinoacetic acid ethyl ester in ml of ethanol for 6 hours yields 2-amino-4-( 3-cyanophenyl l 45.6.7.8- hexahydro-S-oxoquinolinc-3-carhoxylic ncitl ethyl ester of melting point 262C (ethanol/dimcthyllorntamide).

Yield: 56% of theory.

EXAMPLE 55 Upon heating a solution of 9.3 g of 3- bromobenzaldehyde, 5.6 g of cyclohexane-l,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 8 hours, 2-amino-4(3-bromophenyl) 1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxy1ic acid ethyl ester of melting point 255C (ethanol) is obtained.

Yield: 44% of theory.

EXAMPLE 56 Upon boiling a solution of 9.3 g of 2- bromobenzaldehyde, 5.6 g of cyclohexane-l,3dione and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 6 hours, 2-amino-4-(2-bromophenyl)- 1,4,5 ,6,7,8-hexahydro-5-0xoquinoline-3-carboxylic acid ethyl ester of melting point 245C (ethanol) is obtained.

Yield: 46% of theory.

EXAMPLE 57 Upon heating a solution of 8.9 g of 3-carbethoxybenzaldehyde, 5.6 g of cyclohexane-l ,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 4 hours, 2-amino-4-(3-carbethoxyphenyl)-1,4,5,6,7,8 hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 234C (ethanol) is obtained. Yield: 54% of theory.

EXAMPLE 58 wherein R is a heterocyclic ring selected from the group consisting of pyridyl, thenyl, fury] and pyrryl, said heterocyclic ring being unsubstituted or substituted by one or two members selected from the group consisting of lower alkyl, lower alkoxy and halogeno;

R is hydrogen or lower alkyl;

R is lower alkoxy, lower alkoxy(lower alkoxy), al-

kenyloxy of 2 to 4 carbon atoms, alkynyloxy of 2 to 4 carbon atoms, amino, lower alkylamino or di(- lower alkyl)amino; and

.R is lower alkoxy, lower alkoxy(lower alkoxy), al-

kenyloxy of 2 to 4 carbon atoms, alkynyloxy of 2 UNETED STATES PATENT OFFICE CERTIFICATE OF CGRRECTION Patent No. 3,857,849 Dated December 31, 1974 Inventor(s) HORST MEYER ET AL It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the heading of the patent insert Claims priority German patent application P 22 106 74.7, filed in Germany on March 6, 1972.

Signed and sealed this 29th day of April 1975o (SEAL) Attest:

C. MARSHALL DANN Commissioner of Patents and Trademarks RUTH C. MASON Attesting Officer 

1. A COMPOUND OF THE FORMULA:
 2. A compound according to claim 1 wherein R1 is lower alkyl.
 3. The compound according to claim 1 which is 2-amino-6-methyl-4-(fur-2-yl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester.
 4. The compound according to claim 1 which is 2-amino-6-methyl-4-(2-thenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester. 